Studies of ACE-Inhibition and Nitrate Supplementation
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Augmenting Pulmonary Rehabilitation in Chronic Obstructive Pulmonary Disease: Studies of ACE-inhibition and Nitrate Supplementation Katrina Jane Curtis The Muscle Laboratory, Royal Brompton Hospital National Heart & Lung Institute, Imperial College London Submitted for the degree of Doctor of Philosophy (PhD) Imperial College London 1 Declaration of originality The data present in this thesis are the result of my original work. Where appropriate the contribution made by other persons has been appropriately acknowledged. Statement of contribution Contributions were made by Kawah Li and Professor Hugh Montgomery at University College London, who performed the ACE genotyping. In addition, Magda Minnion and Professor Martin Feelisch at the University of Southampton performed the measurement of the plasma nitrate and nitrite levels. Juliet Polkey provided assistance with the isotime data analysis in the nitrate supplementation work. Victoria Meyrick and Bhavin Mehta led the pulmonary rehabilitation programme at the Royal Brompton Hospital, and the team at Harefield Hospital are also acknowledged for their assistance in this respect. Copyright declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives license. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the license terms of this work. Sources of funding The research in the thesis was funded by the Medical Research Council (grant reference MR/J000620/1) and the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, where it was undertaken. 2 Abstract This thesis addresses two approaches to enhancing exercise capacity in chronic obstructive pulmonary disease (COPD). The first is by manipulation of the renin-angiotensin system through angiotensin-converting enzyme (ACE) inhibition to establish if this can augment the response to pulmonary rehabilitation. The second is nitrate supplementation, assessed for its effects on endurance exercise parameters. In a cross-sectional study of 78 patients with at least moderate severity COPD I found no association between ACE genotype and exercise parameters during incremental cycle ergometry, in contrast to previous work from a Chinese group. The role of the renin-angiotensin pathway in skeletal muscle impairment in COPD is likely to be highly complex, and there are both potential beneficial and adverse effects of angiotensin II, and potentially conflicting effects on strength and endurance exercise capacity. The absence of differences in a cross-sectional study do not preclude the possibility that the ACE genotype may influence the response to both training and detraining through physical inactivity, and this remains an area of possible future research. I went on to test the effect of the ACE-inhibitor enalapril on the response to pulmonary rehabilitation, focussing on the change in peak exercise capacity. I undertook a double-blind randomised controlled trial of 80 COPD patients with at least moderate airflow obstruction referred for pulmonary rehabilitation. There was evidence of adequate suppression of ACE activity through both the suppression of serum ACE levels and alteration in blood pressure parameters in the enalapril treated arm. Contrary to expectations the peak power achieved on incremental cycle ergometry increased more in the placebo arm of the study than the ACE-inhibitor treated arm. No significant differences were noted in computed tomography measures of muscle bulk, quadriceps strength or health-related quality of life. Thus, in subjects without a pre-existing clinical indication for ACE-inhibition, use of the ACE-inhibitor enalapril reduced the response to exercise training in COPD. I also conducted a pilot study to investigate the role of acute nitrate supplementation on endurance exercise characteristics and oxygen consumption during endurance exercise in COPD. I recruited 25 subjects into a double-blind, placebo-controlled, single-dose cross-over study. Nitrate supplementation, in the form of beetroot juice at a dose of 12.9 mmoles, significantly lowered resting diastolic blood pressure and isotime pulmonary oxygen consumption. This did not translate 3 into an improvement in endurance time. This preliminary work will provide the basis for further studies, including the potential role of nitrate supplementation in enhancing the response to pulmonary rehabilitation and the role of nitrate supplementation on exercise capacity in individuals with exercise induced hypoxaemia. 4 Acknowledgments I would like firstly to thank my supervisors Nicholas Hopkinson, Michael Polkey and William Man, for both their assistance in conducting this research and their ongoing guidance and support throughout. To Nick I will be forever grateful for his patient support and ongoing ability to educate me about far more than COPD, including politics and world cinema. To Mike whose sagely words of advice and ever open door policy helped me in times of need. I hope we can always remain friends, both professionally and personally. To Will for his great assistance in the writing up process which was so gratefully received. I would also like to thank Mary Morrell for her advice as my mentor and for providing such a strong role model of women in medicine and research. To the friends I made in the Muscle Laboratory, most notably Divya Mohan and Gulam Haji, who not only taught me what I needed to learn but became firm friends during my period in London. I could not have completed this without your help. To others in the laboratory including Sara Buttery, Juliet Polkey, William McNulty, Afroditi Boutou, Matthew Pavitt, Claire Davey, Yogini Raste, Mehul Patel and Benjamin Garfield, thank you for being excellent colleagues who always put the kettle on. To my physiotherapy colleagues, Victoria Meyrick and Bhavin Mehta, thank you for all your help, without which this project would never have been completed, and for teaching me about pulmonary rehabilitation. I would also like to thank Kawah Li and Hugh Montgomery at the Centre for Cardiovascular Genetics at University College London for their help with the ACE genotyping, Magda Minnion and Martin Feelisch at Southampton University for their assistance with the nitrate assays, and Katie O’Brien and Lindsay Edwards at King’s College London for their enthusiasm and interest in the nitrate study. Also thanks to Vibha Teli and Steven Man in the Pharmacy Department of the Royal Brompton Hospital for their help in the MRC randomised controlled trial, and the lung function department of the Royal Brompton Hospital who provided invaluable help and advice. To the patients who took part in the study I shall always be grateful. You taught me how to understand living with a chronic condition far more than any book or research paper ever could, and kept me cheerful throughout. 5 Prizes arising from this thesis American Thoracic Society Abstract Scholarship awarded by the Assembly on Pulmonary Rehabilitation 2016- ‘Angiotensin-Converting Enzyme Inhibition as an Adjunct to Pulmonary Rehabilitation: a Randomised Controlled Trial’ American Thoracic Society Abstract Scholarship awarded by the Assembly on Pulmonary Rehabilitation 2015- ‘Reduced Isotime Oxygen Requirement during Submaximal Exercise in Chronic Obstructive Pulmonary Disease: A Randomised Controlled Trial of Acute Dietary Nitrate Supplementation’ British Lung Foundation Travel Scholarship 2015 for American Thoracic Society Conference Glaxo Smith Kline Sparrows Respiratory Registrars Abstract Competition Finalist 2014- ‘Reduced Isotime Oxygen Requirement during Submaximal Exercise in Chronic Obstructive Pulmonary Disease: A Randomised Controlled Trial of Acute Dietary Nitrate Supplementation’ 6 Publications and abstracts arising from this thesis Angiotensin-Converting Enzyme Inhibition as an Adjunct to Pulmonary Rehabilitation in COPD. Katrina J Curtis, Victoria M Meyrick, Bhavin Mehta, Gulam S Haji, Kawah Li, Hugh Montgomery, William D-C Man, Michael I Polkey, Nicholas S Hopkinson. American Journal of Respiratory and Critical Care Medicine. 2016 Dec 1;194(11):1349-1357. Original research publication. Angiotensin-Converting Enzyme Inhibition as an Adjunct to Pulmonary Rehabilitation: a Randomised Controlled Trial. Katrina J Curtis, Victoria M Meyrick, Bhavin Mehta, Gulam S Haji, Kawah Li, Hugh Montgomery, William D-C Man, Michael I Polkey, Nicholas S Hopkinson. Oral presentation ATS conference 2016, San Francisco, California. Acute Dietary Nitrate Supplementation and Exercise Performance in COPD: A Double-Blind, Placebo-Controlled, Randomised Controlled Pilot Study. Curtis KJ, O'Brien KA, Tanner RJ, Polkey JI, Minnion M, Feelisch M, Polkey MI, Edwards LM, Hopkinson NS. PLoS One. 2015 Dec 23;10(12):e0144504. Original research publication. Reduced Isotime Oxygen Requirement During Submaximal Exercise In Chronic Obstructive Pulmonary Disease: A Randomised Controlled Trial Of Acute Dietary Nitrate Supplementation. K. J. Curtis, K. O'Brien, R. Tanner, M. Feelisch, M. I. Polkey, L. M. Edwards, N. S. Hopkinson. Oral presentation ATS conference 2015, Denver, Colorado. M144 Acute Dietary Nitrate Supplementation Reduces The Oxygen Cost Of Submaximal Exercise In COPD.